Genetic variations in MyD88 adaptor-like are associated with atopic dermatitis

Abstract

Abstract. Toll-like receptors (TLRs) are important pathogenassociated molecular pattern recognition receptors involved in initiating immune responses. The adaptor protein Myd88 adaptor-like (Mal), involved in signaling downstream of TLRs, plays a crucial role in mediating NF-κB activation. The association of Mal polymorphisms with allergic diseases has not previously been defined. The objective of this study was to detect polymorphisms in the Mal gene and to investigate their association with allergic diseases. Mal gene polymorphisms were genotyped in 310 subjects. The functional effects of Mal variants were analyzed in vitro. One Mal polymorphism, c.303 G>A (Q101Q), was found at a significantly lower frequency in atopic dermatitis patients (p=0.016). Q101Q is in linkage disequilibrium with -103 A>G (rs1893352) and c.539 c>T (S180L) (rs8177374) in the HapMap database. The A allele of -103 A>G showed significantly reduced transcription of Mal compared with the G allele. In addition, three rare variants were identified in this study, c.394 G>A (E132K), c.428 G>A (R143Q) and c.570 G>c (E190d), and were shown to lead to loss-of-function of Mal. It is possible that gene polymorphisms in Mal could affect atopic dermatitis by influencing the innate immune system. We show that Q101Q, which is in linkage disequilibrium with -103 A>G and S180L, may play a protective role against atopic dermatitis. Furthermore, we propose that loss-of-function variants of Mal could predispose individuals to atopic dermatitis or other immunological disorders.

Structural Insights into TIR Domain Specificity of the Bridging Adaptor Mal in TLR4 Signaling

“…Moreover, the mutation of another residue (E132) that is close to the AB loop also led to moderately attenuated NF-κB activation in the present study. Similarly, it has been reported that the natural variant E132K leads to a loss of function of Mal [31]. Furthermore, we found that the D87A mutation, which is located in the first βA strand of Mal-TIR near the AB loop, caused severely attenuated NF-κB signaling.…”

“…Recently, several studies have associated natural variants of Mal with various infectious diseases [30], [31], [32], [42], . To further understand the molecular mechanism underlying these associations in the Mal-TIR mutants D96N and S180L, we determined the crystal structures of these mutants.…”

“…The most interesting single nucleotide polymorphism (SNP) is S180L in Mal. Heterozygous carriers of this variant are protected against some infectious diseases, including bacteremia, invasive pneumococcal disease, malaria and atopic dermatitis [30], [31]. In human experimental endotoxemia, individuals heterozygous for S180L produced significantly more proinflammatory cytokines in response to TLR2 and TLR4 ligands in vivo than those homozygous for S180L, and this response is related to an increased resistance to infection [32].…”

“…In human experimental endotoxemia, individuals heterozygous for S180L produced significantly more proinflammatory cytokines in response to TLR2 and TLR4 ligands in vivo than those homozygous for S180L, and this response is related to an increased resistance to infection [32]. Recently, additional rare non-synonymous variants in the coding region of Mal have been found, and these variants include A9P, R13W, S55N, D96N, A100T, E132K, R143Q, R143W, S180L, R184T, E190D, V197I and X222W (a STOP codon mutated to a tryptophan codon) [31], [33], [34], [35]. Among these, D96N, E132K, R143Q and E190D have been reported to cause a loss of function in Mal [31], [33].…”

“…Recently, additional rare non-synonymous variants in the coding region of Mal have been found, and these variants include A9P, R13W, S55N, D96N, A100T, E132K, R143Q, R143W, S180L, R184T, E190D, V197I and X222W (a STOP codon mutated to a tryptophan codon) [31], [33], [34], [35]. Among these, D96N, E132K, R143Q and E190D have been reported to cause a loss of function in Mal [31], [33]. The D96N mutation has also been shown to impair recruitment of MyD88 to the plasma membrane and to influence the post-translational modification of Mal [33].…”